Molecular therapy. Nucleic acidsAug 11, 2026

Using focused ultrasound to deliver lipid nanoparticles for gene editing in the brain

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 12, 2026

Abstract

Focused ultrasound-mediated BBB opening enables efficient delivery of CRISPR-encoding plasmid DNA in brain gene editing.

Lipid nanoparticles (LNPs) can deliver larger genetic materials with reduced immune responses compared to viral vectors.
The use of focused ultrasound (FUS) allows for non-invasive opening of the blood-brain barrier (BBB).
A plasmid containing astrocyte-targeting elements and dual guide RNAs successfully reduced levels of apolipoprotein E4 (APOE4).
Knockdown of APOE4 led to decreased mRNA and protein expression, along with reduced activation of astrocytes and microglia.
FUS-mediated delivery of pDNA-LNPs offers a promising approach for spatially controlled and cell-type-specific brain gene editing.

Simplified

Efficient brain gene editing remains constrained by the lack of delivery platforms that combine efficacy, spatial precision, and translational potential. Compared with viral vectors, lipid nanoparticles (LNPs) offer larger cargo capacity and lower immunogenicity for repeat dosing. However, their brain delivery is restricted by the blood-brain barrier (BBB). Here, we show that focused ultrasound (FUS)-mediated BBB opening enables systemic delivery of CRISPR-encoding plasmid DNA (pDNA)-LNPs for brain gene editing. Using a pDNA construct containing astrocyte-targeting GfaABC1D promoter and dual guide RNAs targeting apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease, we achieved efficient APOE4 knockdown, with reduced APOE4 mRNA and apoE4 protein expression, and attenuated astrocytes and microglial activation. These results establish FUS-mediated pDNA-LNP delivery as a non-invasive, non-viral strategy for brain gene editing that provides spatial control and cell-type-specific expression, while accommodating large genetic payload and enabling repeatable dosing.

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Using focused ultrasound to deliver lipid nanoparticles for gene editing in the brain

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